First Direct Evidence of Neuroinflammation – ‘Encephalitis’ – in ME/CFS

April 29, 2014

Simon McGrath reports on the new study that indicates low-grade encephalitis in ME/CFS …

A small study with just nine patients has captured the attention of patients and researchers alike after reporting direct evidence of inflammation in the brain of ME/CFS patients. The finding was one of the highlights picked out by Professor Anthony Komaroff in his IACFS/ME conference round up.

Back to the future

What makes this study so fascinating is that it provides tantalising evidence supporting not only of current views that inflammation in the brain is central to understanding the disease, but also of Melvin Ramsay’s original name of ‘myalgic encephalomyelitis‘.

Encephalomyelitis is inflammation of the brain and spinal column, and critics of the name pointed to the lack of direct evidence for inflammation of either. This study only looked at the brain, not the spinal column (so could only find encephalitis), but the immune cells found to be activated in the brain are also present in the spinal column.

The study

Dr. Yasuyoshi Watanabe

To see if there is immune activation in the brain, researchers need to look inside the brain — which is not so easy if you want patients to still be alive when your study is done.

The scientists in this study, led by Dr. Yasuyoshi Watanabe from the RIKEN institute in Japan, used PET & MRI imaging to peer into the brain.

What make this study work is the use of tiny quantities of a radioactive tracer that binds to specific proteins that appear on activated microglia (the main immune cells of the brain) but crucially doesn’t bind to non-activated microglia. The marker also binds to activated astrocytes, which play an immune role in the brain. The brains of nine ME/CFS patients meeting both Fukuda and International Consensus Criteria were compared with those of 10 healthy controls.

The results showed that neuroinflammation markers were higher for patients than controls across many brain areas including the thalamus, the pons and the midbrain. They also found that the severity of symptoms correlated with the degree of inflammation in multiple brain regions, particularly for cognitive functioning.

It was the correlation between a biological finding — neuroinflammation — and clinical problems that Komaroff found so exciting about this work, because it suggests a biologically plausible explanation for the symptoms of ME/CFS:

“[If replicated] it would, for me, say that there is a low-grade, chronic encephalitis in these patients, that the image we clinicians have of encephalitis as an acute and often dramatic clinical presentation that can even be fatal has — may have — blinded us to the possibility that there may be that long-lasting — many years long — cyclic chronic neuroinflammation is underlying the symptoms of this illness.”

Intriguingly, the midbrain, thalamus and amygdala — all regions where cognitive problems correlate with neuroinflammation — are also all part of neural circuits involved in awareness, arousal and attention. Concentration problems are typical of ME/CFS, and one of the problems found most consistently in laboratory testing.

Harvard Professor Tony Komaroff on these PET findings, and their potential importance

Starts at 30′ 10″, Q&A re encephalomyelitis @ 37′.

Replication needed

While tantalising, these findings are far from conclusive, as the authors acknowledge. The study has only nine patients, albeit diagnosed with ICC criteria. The tracer used to identify activated immune cells produces a very ‘noisy’ signal, giving rather indistinct readings, and the overall level of neuroinflammation was relatively low.

Although cognitive issues correlated with neuroinflammation in several areas, generally other symptoms, including fatigue, did not significantly correlate with inflammation.

There was almost no sign of inflammation in the prefrontal cortex, the region of the brain most involved in higher cognitive functions, that might be expected to be a problem in ME/CFS. And there was a potential technical weakness in the way the study was run.

Commenting on the neuroinflammation, Komaroff emphasised the need for replication:

“If it were confirmed by multiple other investigators … these data are consistent with [encephalitis], but I would feel more strongly if other labs using same technology came up with the same result.”

The good news is that the authors of this study are already working on a new study using the same patients but with a newer and more sensitive tracer to pick up neuroinflammation. They will address the earlier technical issue, and to make the study more powerful they will also be looking at neurotransmitter activity in the brain, following up their previous findings of neurotransmitter abnormalities.

Hopefully independent groups will try to replicate this finding too – and in the U.K., Dr. Charles Shepherd of the ME Association has already said it would welcome applications to fund a replication attempt.

Microglia — key to ME/CFS?

So neuroinflammation — specifically activation of microglia — correlates with cognitive problems, but how might microglial activation cause the problem?

The most plausible answer is through what is termed ‘sickness behaviour’ — a characteristic set of responses to infection, including fatigue, malaise joint and muscle pain and problems concentrating — which might just sound familiar to ME/CFS sufferers. (‘Sickness behaviour’ is a lousy name for biological phenomenon, as Dr. Dan Peterson has noted).

Microglia are known to play a key role in regulating sickness behaviour, and that’s a big reason this study has attracted so much attention in ME/CFS.

‘Sickness Behaviour’ is driven by biology: infection leads to a rise in pro-inflammatory cytokines in the blood, triggering activation of brain microglia and their production of cytokines. This triggers sickness behaviour.

The fatigue, malaise, problems concentrating, etc., of sickness behaviour help us survive an infection by forcing us to rest so our body can devote all its resources to the energy-greedy immune system.

However, sickness behaviour is normally a short-lived response to an acute infection, designed to temporarily divert resources to ensure a swift recovery. If that doesn’t happen, e.g., if there is a chronic infection, or the process goes wrong, for instance, if microglia remain activated after an infection has been cleared, then sickness behaviour can itself be a problem. ME/CFS may be an example of this.

Cytokines in the spotlight

Cytokines are a key trigger for sickness behaviour, and researchers have often found elevated cytokines in patients, but the findings have been inconsistent and in small studies. The new studies reported on by Dr. Jose Montoya at the Stanford conference and Dr. Mady Hornig at the IACFS/ME conference are helping to firm up these findings in huge cohorts.

Probably the most important piece of work on the role of sickness behaviour — and cytokines — in ME/CFS came from the landmark “Dubbo” studies.

The researchers found that about 11% of those with glandular fever and two other infections developed CFS after six months. And crucially, what predicted the length of the illness (and chance of developing CFS) wasn’t psychological factors, but the severity of the initial ‘acute illness’, or sickness behaviour.

The researchers also showed that those with more active genes for the pro-inflammatory cytokine Interferon-gamma had a more severe sickness behaviour (and longer illness) than those with regular versions, linking cytokine response to sickness behaviour and ME/CFS.

The Dubbo study did not look at inflammation in the brain, but the authors did speculate that the cause of CFS could be long-term activation of microglia and astrocytes. And that is exactly what was found in this new PET imaging study.

As with all research findings, replication is essential, and a new version of the Dubbo study is currently under way in Sydney, Australia.

The new imaging study from Japan has found provisional evidence of activated astrocytes and microglia cells (both types of glial cell) in the brain of ME/CFS patients. This is support for the suggestion from the Dubbo team that ME/CFS develops from certain infections as a result of activation of brain microglia.

Neuroinflammation and Sickness Behaviour the final common path in ME/CFS?

It may prove to be that ‘neuroinflammation’ — i.e., activated microglia in the brain/spinal column — is a common endpoint of numerous triggers, including glandular fever (EBV), other infections, vaccines — or even, as Dr. Lipkin has proposed, disturbances in the microbiome.

Discovering if this is the case — and firming up the finding of neuroinflammation is key — could be a big step forward in understanding and then treating ME/CFS. And those it is still very early days, it is possible this approach could eventually show that Dr Ramsay was right about ‘encephalomyeltitis’.

Another fantastic article Simon. This really is such an interesting area of research and its remarkable how it pulls together many of the other strands that have been discussed for so long in ME/CFS research and those that are only just emerging. I'll be very interesting to see whether any studies confirm these findings as it could be a great finding. Perhaps the reason ME/CFS has been such a difficult nut to crack is because of the relatively low level inflammation being proposed here.

I think if this were to be confirmed the next step would be trying to understand what perpetuates it and I don't doubt that the first port of call for many would be the recent research push towards investigating autoimmunity within ME/CFS, especially given the vast number of conditions associated with autoimmune encephalitis (although admittedly what is being proposed here is an altogether different beast). The interesting thing here is that the ongoing response doesn't appear to be causing gross pathological damage which would likely manifest with somewhat more specific symptoms.

Interesting stuff indeed.

Also I agree that 'Sickness behavior' is a terrible term for such a well acknowledged physiological phenomenon; perhaps one day we'll move to something a little more appropriate like 'Cytokine induced behavioral alteration'.

Another fantastic article Simon. This really is such an interesting area of research and its remarkable how it pulls together many of the other strands that have been discussed for so long in ME/CFS research and those that are only just emerging. I'll be very interesting to see whether any studies confirm these findings as it could be a great finding. Perhaps the reason ME/CFS has been such a difficult nut to crack is because of the relatively low level inflammation being proposed here.

Thanks. Yes, as Tony Komaroff pointed out, encephalitis is normally an acute, dramatic and sometimes fatal condition – whereas these results point to a much lower level of inflammation which simply hasn't been considered by many.

I think if this were to be confirmed the next step would be trying to understand what perpetuates it and I don't doubt that the first port of call for many would be the recent research push towards investigating autoimmunity…

That is the big question (and I thought you might suggest autoimmunity :)). One possibility is that there is an ongoing stimulus, such as a chronic infection – or autoimmunity. Another possibility is that something has gone wrong with regulation of microglia and astrocytes, so that they become 'stuck' in an activated position, so that the neuroinflammation continues long after the original stimulus has been cleared – the 'hit and run' scenario. The Dubbo group propose this possibility, and it is the severity of the initial illness that somehow sets of excessively prolonged activation of microglia in the brain.

Thanks. Yes, as Tony Komaroff pointed out, encephalitis is normally an acute, dramatic and sometimes fatal condition – whereas these results point to a much lower level of inflammation which simply hasn't been considered by many.

That is the big question (and I thought you might suggest autoimmunity :)). One possibility is that there is an ongoing stimulus, such as a chronic infection – or autoimmunity. Another possibility is that something has gone wrong with regulation of microglia and astrocytes, so that they become 'stuck' in an activated position, so that the neuroinflammation continues long after the original stimulus has been cleared – the 'hit and run' scenario. The Dubbo group propose this possibility, and it is the severity of the initial illness that somehow sets of excessively prolonged activation of microglia in the brain.

Interesting, this ties in with how I think that Lyme can share so many similar symptoms, In lyme it is proven that there is a chronic mild encephalitic state of the brain and nervous system, so maybe CFS is derived from this state of inflammation and with each person a possible different underlying cause i.e. Infection, or in some cases auto immune attack? Alongside possible methylation issues that cause someone to be stuck in a set of symptoms where the body cannot resume normal processes again, depleted glutathione and dysregulated immune system, also explains many other things as well..

There are also many other components and tie ins that I have looked into for all of these disease states and it is in some ways incredibly complex but this seems to be a clinical presentation rather then the fundamental root cause. Now if only there was a way to find specific points of dysfunction for each case and work on reversing the vicious cycle for each person. This would be a great discovery, there is still much work to be done!

Simon, what about the possibility of accumulation of environmental toxins in the brain promoting low level inflammation?

This would definitely play a huge component, anyone dealing with chronic illness will have impaired enzyme and physiological activities and all kinds of inflammatory immune system markers, and other sources of impairment. Heavy metal toxicity impairs the basic functioning of the bodily systems and can definitely contribute to a worsening of someones condition, or possibly in some cases the root issue.

A chelation would work great here, however nutritional re balancing and getting the body to detox at a rate of its own seems best, removing amalgams and avoiding high metal toxins would be the safest route, every chelation protocol has its inherit risks and is not worth it in some cases where a person is already so toxic and overwhelmed.. Restoring methylation processes, and glutathione production, alongside a high veggie diet and some lean grass fed meats would work well to get the system re balanced on its own accord. Andy Cutler has a very well known metal de tox protocol which is the only one I would ever trust myself.

That is the big question (and I thought you might suggest autoimmunity :)). One possibility is that there is an ongoing stimulus, such as a chronic infection – or autoimmunity. Another possibility is that something has gone wrong with regulation of microglia and astrocytes, so that they become 'stuck' in an activated position, so that the neuroinflammation continues long after the original stimulus has been cleared – the 'hit and run' scenario. The Dubbo group propose this possibility, and it is the severity of the initial illness that somehow sets of excessively prolonged activation of microglia in the brain.

Well I think it's fairly well known I'm a fan of the autoimmune hypothesis but the interesting thing with this form of neuroinflammation is that there are a plethora of ways to arrive at the same state, as you mention. If this research holds true during replication (and I know that's a very big if!) then we could perhaps be looking at differing sub-groups. It's only logical that if autoimmunity is perpetuating your neuroinflmmation that the treatment would be different than if it was a virus causing it and the same goes for nearly ever different event that could perpetuate it.

since it's in my laywoman's knowledge also the area that controls body temp I'm wondering what the brain would look like during a regular flu with a mild fever

Good question. If it is sickness behaviour then it would be the same basic idea of activated microglia (and astrocytes). Whether the level of neuroinflammation/activation would be the same, I don't know.

As for fever, that turns out to be a separate pathway from sickness behaviour – though again fever is a host response, not something caused by the pathogen: turns out we can generally take the heat better than bugs. One amazing thing I learned on an immunology course I did recently is that reptiles – who are cold-blooded so can't control their body temp – will move to a hotter area if they are sick, say 40 degC, same as a mammalian fever. And experiments have shown moving to the higher temp improves their survival rates.

That is the big question (and I thought you might suggest autoimmunity :)). One possibility is that there is an ongoing stimulus, such as a chronic infection – or autoimmunity. Another possibility is that something has gone wrong with regulation of microglia and astrocytes, so that they become 'stuck' in an activated position, so that the neuroinflammation continues long after the original stimulus has been cleared – the 'hit and run' scenario. The Dubbo group propose this possibility, and it is the severity of the initial illness that somehow sets of excessively prolonged activation of microglia in the brain.

Yes to all the possibilities you mention … I am not familiar with the theory proposed by the Dubbo group, wondering if it is any way similar to what Michal Schwartz talks about here – I find this talk, and her work in general, absolutely fascinating. In this scenario there is a communication breakdown btw microglia and the rest of the immune system, esp blood macrophages (and there can be dozens or hundreds of possible reasons for this breakdown). In any case blood monocytes are needed and constantly being recruited to repair damage in the brain – and they are summoned by the activated microglia.

here are my old notes from her talks, some of it may well be relevant to ME:

She talks about using immune cells to repair injured CNS/brain. By using BLOOD macrophages (as opposed to microglia/macrophages already present in the CNS) and T lympocytes – CD4 positive T cells, they managed to reverse spinal cord injury, PTSD and MD, and stress induced anxiety in mice.

She talks about those 'imported' M2-type activated macrophages (from blood) being protective and healing in cases of spinal cord injury and neurodegeneration etc.

Affinity and regulation is what differentiates T-cells that are autoimmune in pathogenic way and those that are protective

Part of what those good T cells are doing is recruitment of BLOOD monocytes to sites of injury

In injured brain: resident macroglia do the first response job (get activated/inflammed) and by staying activated they recruit blood monocytes to come help. Those newcomer monocytes will then calm down activated resident microglia and terminate their response (this doesn't happen in ME, autism etc but just goes on!??), and this process is dependent on IL-10 ! (if no IL-10 this will not happen)

Their theory: chronic neuroinflammatory disease risk factor is present before visible onset (imo it could even be that prenatal events set the stage). Onset happens when the equilibrium is lost, when the immune system stops responding to need. See slide at 38 minutes for possible reasons why (peripheral loss of immunity etc).

They observed lack of brain plasticity and neurogenesis in immune-deficient animals. They had poor memory, high neurotoxicity etc. In aged animals those that have more memory loss are those whose immune system ages fast, with higher levels of supressive regulatory T-cells! By reducing levels of those Reg T cells they were able to boost brain activity and memory in aged mice.

Great write up Simon. We seem to have taken as slightly different although complementary slant in reporting this. I'm not sure I'd agree with the conclusion that this represent 'encephalitis' though – certainly not the encephalomyelitis as envisaged by Ramsey as discussed here :

I wasn't aware that the Dubbo work was continuing which is great news as a predisposition to an enhanced immune response to common infections could be a key component in a 'multi-hit' scenario (conversely this enhanced response could be a symptom of already primed/activated glia – normal aging involves glial priming and the elderly have an often catastrophic enhanced immune reaction to minor stressors). Another possible contributor is SNPs that result in exaggerated microglial activation. One compelling example is a mouse model of obsessive compulsive disorder (obsessive grooming) where knockout mice displaying this behaviour are 'cured' by transplanting immune cells from wild type (and vice versa). Interesting comments above in this context @natasa778

My own personal view is that this model of neuroinflammation can explain all of the symptoms and is the key to understanding ME/CFS. It may aslo reconcile many previous conflicting findings and the inability to date to identify one pathogen or consistent biomarkers.

As @Legendrew says, there is a vast range of possible triggers that could lead to glial priming and activation. Microglia respond to biological messages which can be classified as PAMPS, DAMPS or 'alarmins' – basically messages signaling organic damage, pathogens or endogenous signaling of metabolic stress respectively. Scientists are only starting to list and characterise alarmins but they include ATP and signaling of fatigue and pain takes place via the purinergic receptors (remember the Lights' gene expression findings?). I wouldn't rule out other metabolic markers such as leptin acting as alarmins either.

As posted on another thread ;

Microglia are the critical convergence point for the many diverse triggers that elicit an adaptive immune response (Figure 1). Stroke, hypoxia, and trauma compromise neuronal survival and indirectly trigger neuroinflammation as microglia become activated in response to the insult in an attempt to limit further injury. Infectious agents activate microglia either through damage to infected cells or direct recognition of foreign (viral or bacterial) proteins. Following exposure to neurotoxins such as the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the dopamine analog 6-hydroxydopamine (6-OHDA), or the pesticide paraquat, microglia become activated and primed. Microglial responses to these toxins may contribute to neuronal dysfunction and eventually hasten neurodegeneration (Czlonkowska et al., 1996; Kohutnicka et al., 1998; Liberatore et al., 1999; Dehmer et al., 2000; Vila et al., 2001). In addition, genetic mutations that give rise to increased production of toxic oligomeric, aggregated/truncated, or oxidized protein species promote sustained activation of microglia and may prime the immune system for aberrant responses to subsequent insults. Regardless of the initiating factor, all of these external or internal stimuli have the potential to trigger a self-perpetuating inflammatory response that, if left unresolved, may contribute to death of vulnerable neuronal populations.

My own feeling is that future research should be aimed at replicating and expanding our understanding of this as the central mechanism and common end point resulting from a range of potential triggers. I am slightly biased though !:)

Simon, what about the possibility of accumulation of environmental toxins in the brain promoting low level inflammation?

Like many things, it is a possibility. If the neuroinflammation pans out – and remember this is just one study on 9 patients – the next step will be finding out what causes the neuroinflammation.

Martial

Interesting, this ties in with how I think that Lyme can share so many similar symptoms, In lyme it is proven that there is a chronic mild encephalitic state of the brain and nervous system, so maybe CFS is derived from this state of inflammation and with each person a possible different underlying cause i.e. Infection, or in some cases auto immune attack?

. Interesting, I didn't know that about an encephalitic state of the brain in Lyme's. Do you know how they showed that?

I agree that the end point of low-grade chronic inflammation could well be a common feature of several diseases, and that's what a number of people are suggesting. I would see the neuroinflammation as a final common pathway, and the sickness behaviour as the clinical manifestation, but either way it could be that several different triggers, and different diseases end up with a similar endpoint. A slightly more nuanced version of this is that certain common symptoms – in particular fatigue – are the result of a shared pathway, but that more than one pathways are in play,

And glad you liked the piece!

Sasha

Great article, @Simon.
I recently had a brain MRI scan which came up negative for signs of inflammation – presumably the kind of low-level inflammation you're talking about here would be invisible on an MRI?

Thanks :). Yes, a MRI scan would definitely NOT pick this up: although the study did use MRI, it was in conjunction with PET, a technique that detects a radioactive tracer, and in this case a tracer specific for activated microglia and astrocytes.

Thank you for your reply, I'm asking because inflammation would mean celldeath (right?) and I know it sounds (and looks, I sent you the link to a video) ridiculous but I think mine are recuperating which wouldn't be possible if…well…..dead. The same thing is happening throughout my body but it manifests differently (brain; májor pressure, eyes; trembling, and so on).

I'm cautious about what the Osaka study actually found – as I wrote on another thead:

"The Osaka City University study is promising but even that need not require actual inflamation of the brain, merely that the usual products of inflammation be present and caused by some as yet unexplained disease process. There's also the possibility that this small Japanese study has revealed something specific to a localised gene variant and replication needs to be done in diverse populations to address that, along with the usual prcesses of replication."

Of course one would hope that nature is abiding by Occam's Razor and the simplest explanation of 'evidence of inflamation = inflamation' is the right one, but in the case of ME I don't think that we can be certain without some very weighty numbers. It's become a sort of accepted coda amongst patients that – "the answer is out there" – and if only researchers had been looking in the right place then 'the answer' to ME would have been found years ago. And again of course that would be ideal because good, focussed and sustained research should be certain of getting the answer. But it may not be like that – ME may just be something that is very difficult to get at, something where there is an awful lot of evidence to be found, but where little or none of the evidence quite means what it is expected to mean.

Great write up Simon. We seem to have taken as slightly different although complementary slant in reporting this.
…

My own feeling is that future research should be aimed at replicating and expanding our understanding of this as the central mechanism and common end point resulting from a range of potential triggers. I am slightly biased though !:)

Thanks :). And if you are talking about mecfs research on neuroinflammation, I totally agree it should be a priority.

Snow Leopard

I'd like to know how the findings of this study compare to that of other medical conditions.

I think for all of this, the first step needed is replication by the original authors using their improved design, which I understand has already started or will soon do so. Then other Qs come into play, including how it compares with other chronic illnesses and with acute infection. As Tony Komaroff said, what's needed is independent confirmation by multiple different labs. I wouldn't normally blog on such a small study, but as the findings tie in with so many other theories, and as an improved version of the study is already planned, I think this study deserves more attention.

Marco

I'm not sure I'd agree with the conclusion that this represent 'encephalitis' though – certainly not the encephalomyelitis as envisaged by Ramsey as discussed here :

Re encephalitis, I took my cue from Tony Komaroff:

Prof Komaroff

"[If replicated] it would, for me, say that there is a low-grade, chronic encephalitis in these patients, that the image we clinicians have of encephalitis as an acute and often dramatic clinical presentation that can even be fatal has — may have — blinded us to the possibility that there may be that long-lasting — many years long — cyclic chronic neuroinflammation is underlying the symptoms of this illness."

As for encephalomyelitis, the microglial and astrocytes that showed up as activated in the brain PET scan are also present in the spinal column, so it's plausible they too are activated – that would need a different PET scan to investigate. Again, this would be low-grade which as I understand it is not what is normally meant by encephalomyelitis. There again, my understanding was that Ramsay used encephalomyelitis because he thought that would explain the clinical symptoms he found (he didn't have direct evidence).

If the neuroinflammation evidence checks out Ramsay may have been on exactly the right lines – that's the only point I'm trying to make. I wouldn't want to push it too far, esp as this is a study on only 9 patients and didn't even look at the spinal column.

I wasn't aware that the Dubbo work was continuing which is great news as a predisposition to an enhanced immune response to common infections could be a key component in a 'multi-hit' scenario (conversely this enhanced response could be a symptom of already primed/activated glia – normal aging involves glial priming and the elderly have an often catastrophic enhanced immune reaction to minor stressors). Another possible contributor is SNPs that result in exaggerated microglial activation.

As @Legendrew says, there is a vast range of possible triggers that could lead to glial priming and activation….

We must talk before I write my next blog! Hugh Perry's hypothesis is about microglial priming, so that people have an exaggerated immune response.

Thanks :). And if you are talking about mecfs research on neuroinflammation, I totally agree it should be a priority.

Yes indeed.

Re encephalitis, I took my cue from Tony Komaroff:

I appreciate that and I agree that its an 'itis' but this type of neuroinflammation is also found in conditions such as post concussion syndrome, complex regional pain syndrome, in normal aging (as previously mentioned) neurodegenerative diseases and in what were considered 'classic' psychiatric disorders such as major depression, bipolar and OCD. It may just be semantics but I doubt few would refer to these conditions as reflecting 'encephalitis' even if neuroinflammation is now recognised as playing a central role.

I appreciate that and I agree that its an 'itis' but this type of neuroinflammation is also found in conditions such as post concussion syndrome, complex regional pain syndrome, in normal aging (as previously mentioned) neurodegenerative diseases and in what were considered 'classic' psychiatric disorders such as major depression, bipolar and OCD. It may just be semantics but I doubt few would refer to these conditions as reflecting 'encephalitis' even if neuroinflammation is now recognised as playing a central role.

the presence of neuroinflammation (which our post-mortem group has already reported in relation to dorsal root ganglionitis – part of the peripheral nervous system) does not necessarily mean that encephalomyelitis is present.
A lot of autoimmune and inflammatory diseases, as well as neurological diseases, have a neuroinflammatory component – but the clinical presentation and pathology is not an encephalomyelitis

I continue to take the view that ME/CFS has a neuroinflammatory component

But I still don’t think that ME/CFS is going to turn out to be what neurologists and pathologists would regard as an encephalomyelitis. – i.e. extensive inflammation involving the brain and spinal cord

So to avoid confusion I will stick with neuroinflammation. However, I do think that Ramsay's implicit point, that the symptoms indicated a problem in the brain, may eventually prove right.

Well I think it's fairly well known I'm a fan of the autoimmune hypothesis but the interesting thing with this form of neuroinflammation is that there are a plethora of ways to arrive at the same state, as you mention. If this research holds true during replication (and I know that's a very big if!) then we could perhaps be looking at differing sub-groups. It's only logical that if autoimmunity is perpetuating your neuroinflmmation that the treatment would be different than if it was a virus causing it and the same goes for nearly ever different event that could perpetuate it.

I'm not suggesting this is a treatment for ME/CFS or any other case of neuroinflammation, but it does suggest another route to treatment, even if it wasn't treating the cause.

Another possibility is that the chronic neuroinflammation is chronic because of a problem with the microglia, and not because of any stimulus outside the brain, and again in that case a microglial inhibitor might be appropriate. Though of course, you need your microglia to get active some of the time, that's what they are there for.

Probably the most important piece of work on the role of sickness behaviour — and cytokines — in ME/CFS came from the landmark "Dubbo" studies.

The researchers found that typically, 20% of those with glandular fever and two other infections developed CFS after six months. And crucially, what predicted the length of the illness (and chance of developing CFS) wasn't psychological factors, but the severity of the initial 'acute illness', or sickness behaviour.

I'm a little concerned about this bit, do you know if the scans were analyzed blind ?

I'd imagine you would compare the scans of controls and patients alongside one another and it would allow you to clean up a lot of the 'noise', it's far from a perfect way to analyse this kind of data but it lets you see on a qualitative level whether there is any significant difference which is what I believe this study is reporting.

I'm a little concerned about this bit, do you know if the scans were analyzed blind ?

Not sure, but they did prespecify which areas they considered:

Image Data Analysis
All 11C-(R)-PK11195 BPND images were normalized to the Montréal
Neurologic Institute space, smoothed with an isotropic 8-mm
gaussian kernel, and analyzed by Statistical Parametric Mapping 5
software (SPM5; Wellcome Department of Cognitive Neurology) using
a categoric design. The between-group comparison (CFS/ME
patients vs. healthy controls) of 11C-(R)-PK11195 BPND and correlation
analysis of 11C-(R)-PK11195 BPND values and clinical scores
were performed on a voxel-by-voxel basis using t statistics with the
statistical threshold set at a P value of less than 0.005 at the voxel level
and a P value of less than 0.05 with a correction for multiple comparisons
at the cluster level for the entire brain (familywise error). The
regions of interest for the cingulate cortex, hippocampus, amygdala,
thalamus, midbrain, and pons were defined from the Wake Forest
University PickAtlas (21) and applied to the smoothed images.

Does this help? there is more like it….

Dolphin

Another great article, Simon.

Small point:[I got the numbers wrong in the blog :bang-head:]
What the study found was:

Thanks on both counts. I was finishing the blog off yesterday and was having a rough one – I was sure the figure was around 12% but could only find one suggesting 20% so lazily went with that. Blog now corrected.

soofke

Thank you for your reply, I'm asking because inflammation would mean celldeath (right?) and I know it sounds (and looks, I sent you the link to a video) ridiculous but I think mine are recuperating which wouldn't be possible if…well…..dead. The same thing is happening throughout my body but it manifests differently (brain; májor pressure, eyes; trembling, and so on).

Activation of the microglia (or astrocytes) themselves does not cause their cell death. Their activation will lead to other changes which may or may not lead to cell death/apoptosis for other cells – I think it would depend on other things too, such as other signalling molecules in the micro environment.

its worth looking into memantine as a treatment for inflammation in ME as this drug has been around awhile and can be repurposed, so no having to wait for long trials and studies for its approval, possibly get a doctor now to prescribe it off label.

Memantine has effects on lowering tnf as well as nmda/glutamate, another cause of inflammation. It also helps increase dopamine which is useful for increasing mood and energy, decreasing pain and many other functions. Its also known to increase cortisol in certain parts of the brain which would also enhance energy. The nmda antagonist effects can also improve gaba sensitivity, so maybe help those with that tired wired feeling??

I think its an interesting drug that could be very useful in this reguard??

I think the evidence of neuro-inflammation, whether or not you consider that to be encephalitis, goes back to 1955. After the outbreaks in Adelaide, Australia, in the late 1940s they did some research. One line of research injected patient blood into animals. In 1955 it was published that the blood in monkeys resulted in particular kinds of spinal lesions, with immune infiltration. That is, I think not coincidentally, the kind of thing they have found in ME autopsy results.

In inflammation there is growing evidence that brain cells do not so much die as become dormant. So long as inflammation persists they do not function. Remove the inflammation and they have restored function. This is still a new and controversial area though.

Also, what are the implications for treatment once this inflammation is discovered?

Is this an article I should be showing to my neurologist or pain management doctor?

Hi Womble
This is very much an early finding that needs replication, not something that would be helpful in the clinic. I think it's too early to show to your neurologist or pain management doctor, though if the findings are independently replicated those replications would be worth mentioning. I'm afraid it would be another step again (probably a big one) from establishing that neuroinflammation is important in the illness to actually having a treatment.

Last year I saw a neurologist at NYU, well 2 to be exact. We did a PET scan and found decreased metabolism through-out my brain, the radiologist was so alarmed she paged him and said, "I've never seen anything like this in a 20 – something female, this is what'd I'd expect to see in an elderly patient with severe Alzheimer's". They looked at extensive labs from UM and my pro-inflammatory cytokines were through the roof.

They said they thought I had neuro-inflammation and we did CT scan which also came back grossly abnormal. I received a diagnosis of "primary autoimmunity and clinical encephalitis". These are not quack doctors they are NYU NEUROLOGISTS. My insurance covered an 11 day stay at NYU to get IVIG, I had 4 infusions, a lumbar puncture that went bad and that I still don't have results from, ended up with LP leak and stayed in hospital for 11 days – there was nothing more brutal than everything I went through.

My insurance company cancelled ivig and have denied all appeals to continue, now my neurologist has dropped me as a result. We have PROOF of inflammation, not just in one spot, all over my fu**ing brain, yet I can't get anyone to help me. I contacted the Autoimmune encephalitis alliance and they recommended some doctor from mayo – I've been there 4 times and was told every time to see a psychiatrist.

I do think I have M.E. but I also have terrible depression and OCD and insomnia, the diagnosis eventually became "neuro-psychiatric autoimmune encephalitis" but my records still say clinical encephalitis. Just thought I'd add my story to show and prove that yes we have neuro-inflammation and in my case I have all signs of auto-immunity, unfortunately it's making me deathly ill and I can't find anyone to help me or they don't know what to do; I really thought ivig would help but insurance won't cover it.

Another possibility is that the chronic neuroinflammation is chronic because of a problem with the microglia, and not because of any stimulus outside the brain, and again in that case a microglial inhibitor might be appropriate. Though of course, you need your microglia to get active some of the time, that's what they are there for.

Guess we need the 'Big If' of replication sorted first!

When I first got hit with encephalitis and subsequently M.E. I was seeing Dr Romeo Mariano in Monetary, CA, a psychiatrist who also practices neuroendocrinology. He was the first one to recognise my symptoms and pegged me 100% for brain. inflammation.

He did state, however, that brain inflammation is a much different monster than inflammation in the body and described trying to stop it as akin to "trying to stop a speeding train without any brakes" He said that no matter what the initial offender, once microgliol activation reaches a certain level it can go on for the rest of your life unless direct action is taken.

Last year I saw a neurologist at NYU, well 2 to be exact. We did a PET scan and found decreased metabolism through-out my brain, the radiologist was so alarmed she paged him and said, "I've never seen anything like this in a 20 – something female, this is what'd I'd expect to see in an elderly patient with severe Alzheimer's". They looked at extensive labs from UM and my pro-inflammatory cytokines were through the roof. They said they thought I had neuro-inflammation and we did CT scan which also came back grossly abnormal. I received a diagnosis of "primary autoimmunity and clinical encephalitis". These are not quack doctors they are NYU NEUROLOGISTS. My insurance covered an 11 day stay at NYU to get IVIG, I had 4 infusions, a lumbar puncture that went bad and that I still don't have results from, ended up with LP leak and stayed in hospital for 11 days – there was nothing more brutal than everything I went through. My insurance company cancelled ivig and have denied all appeals to continue, now my neurologist has dropped me as a result. We have PROOF of inflammation, not just in one spot, all over my fu**ing brain, yet I can't get anyone to help me. I contacted the Autoimmune encephalitis alliance and they recommended some doctor from mayo – I've been there 4 times and was told every time to see a psychiatrist. I do think I have M.E. but I also have terrible depression and OCD and insomnia, the diagnosis eventually became "neuro-psychiatric autoimmune encephalitis" but my records still say clinical encephalitis. Just thought I'd add my story to show and prove that yes we have neuro-inflammation and in my case I have all signs of auto-immunity, unfortunately it's making me deathly ill and I can't find anyone to help me or they don't know what to do; I really thought ivig would help but insurance won't cover it.

thanks for sharing your story. Lumbar punctures are said to be painful when gone well, feel sorry that yours went bad, the pain must have been bad, hope they atleast treated your pain???

So are u undertaking any treatments for this neuro inflammation? Im guessing some antidepressants would have anti inflammatory effects as well as certain anticonvulsants??

I also had various MRIs and MRAs which came back clear, but then went on to get a SPECT scan where it showed massive hypoperfusion. Much like
@CallieAndToby stated, the doctor said he has never seen a case so bad, especially in a 28 year old. He said it was akin to mid-late stage Alzheimer's or dementia. However, as satisfying as it was to me to have validation of my problems it didn't help with any treatments.

I then brought these results, along with the white blood cells in my spinal fluid found from a lumbar puncture, back to the neurologists that I saw at Yale (who told me I was a psychiatric patient) and they completely dismissed it. They told me that a SPECT and PET are completely unreliable and "will change if you have a bad hair day" They again referred me to a psychiatrist, this time because "your obsessed with symptoms"

All this makes me think its a waste of time to go to doctors to try to get help. I still can't fathom why proof of problems is dismissed as irrelevant, seen in the general population or psychiatric. I just don't get it.

I'm not suggesting this is a treatment for ME/CFS or any other case of neuroinflammation, but it does suggest another route to treatment, even if it wasn't treating the cause.

Dr Younger listed potential microglial inhibitors that he thinks may be worth investigating at the Stanford and IACFS/ME conferences. Other than naltrexone I don't think most have been studied in fibromyalgia or ME but I think several are very promising. For example, I know many people are using minocycline for its neuroprotective qualities. The list is split into prescription drugs and supplements (primarily from chinese medicine.)
The full list is at http://forums.phoenixrising.me/inde…-me-21-march-day-two.29098/page-3#post-443598

I have only tried a few items on that list and have found ganoderma lucidum (reishi) to be the most obviously effective. As an extra bonus, reishi also appears to increase NK cell cytotoxicity.

Last year I saw a neurologist at NYU, well 2 to be exact. We did a PET scan and found decreased metabolism through-out my brain, the radiologist was so alarmed she paged him and said, "I've never seen anything like this in a 20 – something female, this is what'd I'd expect to see in an elderly patient with severe Alzheimer's". They looked at extensive labs from UM and my pro-inflammatory cytokines were through the roof. They said they thought I had neuro-inflammation and we did CT scan which also came back grossly abnormal. I received a diagnosis of "primary autoimmunity and clinical encephalitis". These are not quack doctors they are NYU NEUROLOGISTS. My insurance covered an 11 day stay at NYU to get IVIG, I had 4 infusions, a lumbar puncture that went bad and that I still don't have results from, ended up with LP leak and stayed in hospital for 11 days – there was nothing more brutal than everything I went through. My insurance company cancelled ivig and have denied all appeals to continue, now my neurologist has dropped me as a result. We have PROOF of inflammation, not just in one spot, all over my fu**ing brain, yet I can't get anyone to help me. I contacted the Autoimmune encephalitis alliance and they recommended some doctor from mayo – I've been there 4 times and was told every time to see a psychiatrist. I do think I have M.E. but I also have terrible depression and OCD and insomnia, the diagnosis eventually became "neuro-psychiatric autoimmune encephalitis" but my records still say clinical encephalitis. Just thought I'd add my story to show and prove that yes we have neuro-inflammation and in my case I have all signs of auto-immunity, unfortunately it's making me deathly ill and I can't find anyone to help me or they don't know what to do; I really thought ivig would help but insurance won't cover it.

Another reason I get infuriated at the arrogant twits explaining that "Aren't you glad you have Obamacare/it would be so much better with single payer!1!". They like hearing themselves talk, but helping YOU is not anywhere on their mental map.

You need a family member to help you fuss with insurance. It can be done, but probably not while having an encephalitic condition. I know I can't manage that level of bureaucratic combat.

I'm interested in the facts hat your insurance covered some IVIG. If I may ask, what was it for specifically? Parvo? I also had/have encephalitis and would love to get IVIG for my parvo and m. Pneumoniae but I need a doctor to order it which has been impossible so far. I was admitted to Yale for 4 days and they sent me packing with a diagnosis of depression.

I also had various MRIs and MRAs which came back clear, but then went on to get a SPECT scan where it showed massive hypoperfusion. Much like
@CallieAndToby stated, the doctor said he has never seen a case so bad, especially in a 28 year old. He said it was akin to mid-late stage Alzheimer's or dementia. However, as satisfying as it was to me to have validation of my problems it didn't help with any treatments.

I then brought these results, along with the white blood cells in my spinal fluid found from a lumbar puncture, back to the neurologists that I saw at Yale (who told me I was a psychiatric patient) and they completely dismissed it. They told me that a SPECT and PET are completely unreliable and "will change if you have a bad hair day" They again referred me to a psychiatrist, this time because "your obsessed with symptoms"

Wow, I'm speechless.

How much evidence do they need before they recognize this as a legitimate medical problem?

But yeah, it doesn't sound like any treatments are on the horizon for this, despite this new evidence.

Hi Womble
This is very much an early finding that needs replication, not something that would be helpful in the clinic. I think it's too early to show to your neurologist or pain management doctor, though if the findings are independently replicated those replications would be worth mentioning. I'm afraid it would be another step again (probably a big one) from establishing that neuroinflammation is important in the illness to actually having a treatment.

One to watch for the future, though.

Might encyphalitis be a way of explaining my pain syndrome at least?

When the doctors ask me what kind of pain I'm having, and I just describe it as a "nerve ending pain" or an "inflammation", they act clueless.

Maybe neuro-inflammation would clarify it for them? Cause it feels like my brain is burning, that is literally what it feels like.

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